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M Nauck

Publications and source records attributed to M Nauck.

At least 73 records · Page 4Linked to original sources
PubMed1996

[Combination antihypertensive therapy in patients with an increased risk profile].

BACKGROUND: Antihypertensive drug combinations have two major advantages: First, dosage of the single components can be reduced, and second, putative side effects can be minimized. Therefore, we analysed in a cohort of patients with multiple cardiovascular risk factors the metabolic effects of two fixed antihypertensive drug combinations. PATIENTS AND METHODS: 225 patients with essential hypertension (dBP > or = 95 < or = 115 mm Hg) and adipositas (BMI 30.6 +/- 2.5) were randomly treated during 6 months with either quinapril and hydrochlorothiazide (HCTZ) or with metoprolol and hydrochlorothiazide. Compared with healthy controls, patients exhibited significant elevated concentrations of triglycerides (226 +/- 86 vs. 146 +/- 73 mg/dl) and fasting insulin (22.2 +/- 1.8 vs. 9.8 +/- 4.6 microU/ml). RESULTS: The antihypertensive effects and the tolerance of both substances were good and comparable after 3 and 6 months. Serum triglycerides increased during metoprolol/hydrochlorothiazide treatment (230 +/- 81 vs. 244 +/- 185 mg/dl; median 174 vs. 204; + 17%), as well as during treatment with quinapril/hydrochlorothiazide (222 +/- 155 vs. 235 +/- 162 mg/dl; median 166 vs. 174; + 5%). Fasting blood glucose levels, insulin, fructosamine, HbA1c and free fatty acids remained unchanged. In a subgroup of 88 postmenopausal women with upper body obesity (WHR > 0.85) treatment with quinapril/hydrochlorothiazide normalized the VLDL-triglyceride/VLDL-cholesterol ratio (3.8 vs. 5.9, p < 0.05), whereas the ratio only increased from 3.6 to 4.2 in the metoprolol/hydrochlorothiazide group. These changes in the ACE-inhibitor group were due to a decrease in VLDL-cholesterol (41.4 +/- 4.2 vs. 33.9 +/- 9.6). CONCLUSION: These data demonstrate that quinapril or metoprolol in combination with hydrochlorothiazide do not differ significantly with regard to their effects on blood-pressure lowering, lipoprotein profile, and glucose metabolism. Only in the subgroup of adipose postmenopausal women, the modulated VLDL-composition might suggest the elimination of atherogenic VLDL-remnants/IDL during quinapril/hydrochlorothiazide treatment.

Adult↗
PubMed1996

Platelet-activating factor exerts mitogenic activity and stimulates expression of interleukin 6 and interleukin 8 in human lung fibroblasts via binding to its functional receptor.

Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator of the lung. In this study, we demonstrate that PAF receptor mRNA and protein is expressed by human lung fibroblasts. Interaction of PAF with its specific receptor resulted in increases of tyrosine phosphorylation of several intracellular proteins, indicating that the PAF-receptor might be functionally active. PAF-induced transcription of protooncogenes c-fos and c-jun as well as of interleukin (IL)-6 and IL-8 genes in human fibroblasts. Transcription of the interleukins was followed by secretion of the respective proteins. Moreover, PAF enhanced proliferation of fibroblasts in a concentration-dependent manner. Using signaling inhibitors, we demonstrate that PAF-induced transcription of the c-fos, IL-6, and IL-8 genes, as well as proliferation, require activation of pertussis toxin-sensitive G proteins, tyrosine kinases, and protein kinase C (PKC). In contrast, transcription of c-jun was blocked by pertussis toxin, but not by inhibitors for tyrosine kinases or PKC. These data suggest that PAF stimulates distinct signaling pathways in human lung fibroblasts. In addition, the activation of human fibroblasts by PAF leads to enhanced proliferation and to the expression of proinflammatory cytokines, which may contribute to the pathophysiological changes in pulmonary inflammation.

Cells, Cultured↗
PubMed1996

Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with increased plasma angiotensin-converting enzyme activity but not with increased risk for myocardial infarction and coronary artery disease.

BACKGROUND: Previous research has shown that the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene is a major determinant of plasma ACE activity. It has been suggested that persons with the DD genotype (those who express, on average, the highest levels of circulating ACE) have an increased risk for myocardial infarction and coronary artery disease, particularly if they are otherwise at low risk. Subsequent studies, however, have not confirmed that ACE I/D gene polymorphism is a risk factor for coronary artery disease and myocardial infarction. OBJECTIVE: To investigate the association between the I/D polymorphism of the ACE gene and the risk for coronary artery disease and myocardial infarction in patients in whom coronary artery disease status was documented by angiography. DESIGN: Cross-sectional study. SETTING: University medical center. PATIENTS: 209 male case-patients with coronary artery disease and 92 male controls without coronary artery disease, as documented by coronary angiography. MEASUREMENTS: Assessment of the cardiac risk profile by questionnaire; classification of patients by the degree of coronary artery stenosis; levels of lipoproteins, apolipoproteins, and fibrinogen; and ACE I/D gene polymorphism assessed by polymerase chain reaction amplification. RESULTS: Plasma ACE activity was significantly associated with ACE I/D gene polymorphism. The ACE genotype was not associated with the presence of coronary artery disease or myocardial infarction. If a recessive effect of the D allele was assumed (DD compared with DI and II), the relative risk was 1.00 (95% CI, 0.76 to 1.30) for coronary artery disease and 1.03 (CI, 0.77 to 1.38) for myocardial infarction. Results of analyses were also negative when a dominant effect of the D allele was assumed and when low-risk subgroups were examined. The established risk factors age and apolipoprotein B level emerged as the most important risk predictors in multivariate analyses, followed by diastolic blood pressure and fasting glucose levels. CONCLUSIONS: In an angiographically defined study sample, ACE I/D gene polymorphism was not associated with an increased risk for coronary artery disease or myocardial infarction, despite its effects on plasma ACE activity.

Aged↗
PubMed1996

Induction of interleukin 6 and interleukin 8 expression by Broncho-Vaxom (OM-85 BV) via C-Fos/serum responsive element.

BACKGROUND: Broncho-Vaxom (OM-85 BV) increases the resistance of the respiratory tract to bacterial infections by modulating host immune responses. The compound increases serum IgG levels but decreases IgE levels in patients suffering from chronic bronchitis or chronic obstructive pulmonary disease. It increases concentrations of gamma-interferon (IFN-gamma), IgA, and interleukin (IL)-2 in bronchoalveolar lavage fluid of patients with bronchitis. Treatment with OM-85 BV increases the number of T helper and natural killer cells. In this study the effects of OM-85 BV on transcription of cytokines is investigated in human lung fibroblasts. METHODS: Transcription and synthesis of IL-6 and IL-8 were assessed in cultured primary human lung fibroblasts using standard methods of Northern blot analysis for the level of mRNAs and enzyme linked immunosorbent assay for proteins. RESULTS: Broncho-Vaxom (OM-85 BV) at different concentrations induced transcription of IL-6 and IL-8. The effect of the drug on transcription of IL-6 and IL-8 genes correlated with secretion of the proteins into cell supernatants. OM-85 BV-dependent expression of the interleukin genes involved C-Fos/serum responsive element (C-Fos/SRE). CONCLUSIONS: The data suggest that the various immunopharmacological activities of OM-85 BV that have been described in clinical studies may be explained by its ability to induce expression of IL-6 and IL-8.

Adjuvants, Immunologic↗
PubMed1996

VLDL and LDL metabolism in human and rat mesangial cells.

Human low-density lipoprotein (LDL) is taken up by rat mesangial cells in a receptor-dependent manner, although lipoprotein metabolism and lipoprotein receptors differ substantially between rodents and humans. We therefore compared binding and uptake kinetics as well as intracellular cholesterol metabolism of apoB- and apoB,E-containing lipoproteins in rat and human mesangial cells. Uptake of very-low-density lipoprotein (VLDL) and LDL in both human and rat mesangial cells occurred in a receptor-specific, concentration-dependent manner and the process was saturable. However, LDL uptake specificity, receptor affinity and maximal degradation capacity was remarkably lower in rat than in human mesangial cells. Exposure of cells to LDL suppressed intracellular sterol synthesis more effectively in the human than in the rat cell line (87 vs. 36%, respectively). Additionally, cholesteryl ester formation was enhanced 23-fold by LDL in human as compared to rat mesangial cells. In contrast, degradation capacities of VLDL were higher in rat and uptake specificity as well as receptor affinity were similar. Inhibition of intracellular cholesterol synthesis and oleate formation rate by VLDL occurred to a similar extent in both cell lines. The data demonstrate that mesangial cell uptake of apoB-containing lipoproteins depends on the species investigated, whereas apoE-rich lipoprotein particles are taken up independent of species. Therefore, human mesangial cells should be preferred over rat mesangial cells when investigating lipoprotein metabolism to elucidate the potential role of lipoproteins in mediating glomerular injury and progression of renal disease in man.

Acetates↗
PubMed1996

Homogeneous assay for direct determination of high-density lipoprotein cholesterol evaluated.

We evaluated a new homogeneous assay for quantifying high-density lipoprotein cholesterol (HDL-C). The assay included four reagents: polyethylene glycol for "wrapping" chylomicrons, very-low-density lipoproteins (VLDL), and low-density lipoproteins (LDL); antibodies specific for apolipoprotein (apo) B and apo C-III to produce aggregates of chylomicrons, VLDL, and LDL; enzymes for the enzymatic cholesterol determination of the noncomplexed lipoproteins with 4-aminoantipyrine as the color reagent; and guanidine salt to stop the enzymatic reaction and to solubilize the complexes of apo B-containing lipoproteins, which would otherwise interfere with the reading of absorbance. The total CVs of the new method ranged between 2.4% and 8.4%. The HDL-C values (y) were in good agreement with those by a comparison phosphotungstic acid/MgCl2 method (x): y= 0.987x + 17.2 mg/L (68th percentile of the residuals on the regression line= 21.49, r= 0.970). At triglyceride concentrations of 20 g/L (Intralipid) the homogeneous HDL-C concentrations increased by 2%. Hemoglobin markedly increased the results, whereas bilirubin reduced them. The homogeneous HDL-C assay was easy to handle and allows full automation. This test should considerably facilitate the screening of individuals at an increased risk of cardiovascular disease.

Apolipoprotein A-I↗
PubMed1996

Lipoprotein(a) in patients with the nephrotic syndrome: influence of immunosuppression and proteinuria.

Lipoprotein(a) [Lp(a)] is a plasma lipoprotein whose structure and composition closely resemble that of low-density lipoproteins, but contains an additional protein called apolipoprotein(a) [apo(a)]. Factors which modulate plasma Lp(a) concentrations are poorly understood. The influence of nephrotic syndrome on Lp(a) levels was investigated in 103 patients with nephrotic syndrome: 72 with primary kidney disease and 31 with diabetic nephropathy. Nephrotic patients had significantly higher Lp(a) levels (mean 63 +/- 7 mg/dl; median 42 mg/dl) compared with controls (mean 22 +/- 2 mg/dl; median 8 mg/dl). Fifty-seven percent of the patients and 22% of the controls had values greater than 30 mg/dl. Within all apo(a) isoform classes, higher concentrations of Lp(a) were seen in the nephrotic patients compared with controls. In 17 patients with primary kidney disease remission of the nephrotic syndrome was induced by immunosuppressive treatment and Lp(a) concentration dropped in parallel with the reduction of proteinuria (pretreatment mean, 98 +/- 9 mg/dl vs. remission mean, 25 +/- 5 mg/dl). In 9 patients where multiple measurements were done, multiple regression analysis showed a strong relation of Lp(a) with the amount of proteinuria (p < 0.01). We conclude that most patients with the nephrotic syndrome have Lp(a) concentrations which are substantially elevated compared with control subjects of the same apo(a) isoform. Because Lp(a) concentrations are substantially reduced when remission of the nephrotic syndrome is induced by immunosuppressive drugs, it is likely that nephrotic syndrome directly results in elevation of Lp(a). The high levels of Lp(a) in nephrotic syndrome could potentially cause glomerular injury as well as increase the risk of atherosclerosis and thrombotic events associated with this disorder.

Adolescent↗
PubMed1996

Cholesterol metabolism in glomerular cells: effect of lipoproteins from nephrotic patients.

Although hyperlipidemia is a well recognized complication of the nephrotic syndrome, the precise metabolism of human lipoproteins by human glomerular cells and the effects of abnormalities in lipid and protein composition on this process have not been defined. This study examined the effects of apoB-100 containing low-density-lipoprotein (LDL) and apo B,E, containing intermediate-density lipoprotein (IDL), isolated from patients with the nephrotic syndrome (n = 6), on intracellular sterol synthesis and cholesterol esterification by human glomerular epithelial and mesangial cells. For comparison studies, human skin fibroblasts and Hep G2 cells were used. In the patients, serum LDL cholesterol level was increased threefold and IDL tenfold as compared to healthy subjects. LDL of nephrotic patients showed no differences in lipid/protein composition as compared to control LDL but IDL contained 58% more cholesterol than IDL from healthy controls. Therefore, nephrotic and control LDL showed identical inhibition of intracellular sterol synthesis and similar cholesteryl ester formation in all the four cell types. In contrast, cholesterol-rich IDL of nephrotic patients suppressed intracellular sterol synthesis more effectively than control IDL. The cholesterol esterification rate of IDL from patients was enhanced three fold on average as compared to control IDL. The various cell types differed in their rate of LDL esterification. The data indicate that the enhanced inhibition of intracellular sterol synthesis and cholesterol esterification by apo E-containing cholesterol-ester-rich IDL, which accumulate in nephrotic patients, may render these lipoproteins possible candidates for glomerular lipid deposition and progressive renal injury.

Adult↗
PubMed1996

Therapeutic potential of glucagon-like peptide 1 in type 2 diabetes.

GLP-1 is a peptide hormone which has been shown to have a variety of antidiabetic actions that could help to reduce glycaemia especially in Type 2 diabetic patients: (1) It produces glucose-dependent stimulation of insulin secretion, and (2) inhibition of glucagon secretion; (3) there is evidence that it increases the rate of (pro)-insulin synthesis and it may also increase insulin sensitivity; (4) it slows the rate of gastric emptying for liquid meals, and possibly also for solid meals; (5) it appears to act within the central nervous system to suppress appetite. These actions of GLP-1 oppose a number of the abnormalities that are commonly observed in patients with Type 2 diabetes. Many facets of Type 2 diabetes, therefore, could be envisaged as a consequence of a lack of GLP-1 effects; they appear to be corrected by the exogenous administration of this gut peptide in short-term experiments. Future activities will aim at the therapeutic exploitation of this pharmacological potential by modifying GLP-1 and its ways of administration to suit the practical needs of patients with Type 2 diabetes.

Animals↗
PubMed1996

Is the determination of LDL cholesterol according to Friedewald accurate in CAPD and HD patients?

Lipid abnormalities are a major cause of accelerated atherosclerosis in patients with end-stage renal disease. In many clinical laboratories, the concentration of low density lipoproteins (LDL), the most atherogenic lipoprotein fraction, is estimated by calculating LDL cholesterol according to Friedewald. Hypertriglyceridemia, a common finding in uremic patients, is a main limitation to the use of the Friedewald formula, and the estimation of LDL cholesterol may, therefore, not be reliable in these patients. As accurate quantitation of LDL cholesterol is needed to decide on the initiation of lipid lowering therapy, we have evaluated the accuracy of the Friedewald formula in 171 patients on continuous ambulatory peritoneal dialysis (CAPD), 136 hemodialysis (HD) patients and 887 clinically healthy individuals by comparing it with a combined ultracentrifugation and precipitation 'reference' method. When we excluded sera with total triglycerides above 400 mg/dl [4.56 mmol/l], the Friedewald formula correlated excellently with the reference method; non-parametric correlation coefficients were 0.976, 0.971, and 0.956 in clinically healthy individuals, CAPD and HD patients, respectively. In the control individuals, the Friedewald formula produced slightly lower concentrations of LDL cholesterol than the reference method (means: 142 +/- 40 mg/dl vs 150 +/- 39 mg/dl or 3.68 + 1.04 mmol/l vs. to 3.89 + 1.01 mmol/l, respectively). This was also true in HD patients (means: 145 +/- 51 vs. 146 +/- 49 mg/dl or 3.76 +/- 1.32 vs. 3.78 +/- 1.27 mmol/l, respectively), but not in CAPD patients (means: 165 +/- 50 vs. 162 +/- 47 mg/dl or 4.27 +/- 1.30 vs. 4.20 +/- 1.22 mmol/l). Our data show that, unlike in other forms of secondary dyslipoproteinemia, the Friedewald formula is sufficiently reliable in patients with end-stage renal disease. Much the same, however, as in control individuals, other methods to quantify LDL cholesterol like ultracentrifugation or lipoprotein electrophoresis are recommended when serum triglycerides exceed 400 mg/dl [4.56 mmol/l].

Case-Control Studies↗
PubMed1995

Intracellular interleukin 6 mediates platelet-derived growth factor-induced proliferation of nontransformed cells.

The functional relevance of interleukin 6 (IL-6) in platelet-derived growth factor (PDGF)-induced cell growth was evaluated in cultures of human fibroblasts, vascular smooth muscle cells, and mesangial cells. The three isoforms of the PDGF--namely, PDGF-AA, -AB, and -BB--induced the expression of the IL-6 gene and proliferation of the nontransformed cells. PDGF-induced transcription, translation, and secretion of IL-6 were diminished in the presence of IL-6 antisense oligonucleotides. While neutralizing anti-IL-6 antibodies failed to affect the growth factor-dependent cell proliferation, IL-6 antisense oligonucleotides inhibited cell division. In addition, IL-6 antisense oligonucleotides abolished PDGF-induced transcription of the genes coding for the cell division cycle 2-related protein (CDC2) and proliferating cell nuclear antigen (PCNA), both of which are regulated in a cell cycle-dependent manner. It is concluded that PDGF-dependent proliferation of nontransformed cells involves the action of intracellular IL-6.

Base Sequence↗
PubMed1995

Ca(2+)-channel blockers modulate the expression of interleukin-6 and interleukin-8 genes in human vascular smooth muscle cells.

Ca(2+)-channel blockers at therapeutic concentrations were shown to modulate several processes underlying inflammation, such as growth factor-mediated activation of genes coding for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in human vascular smooth muscle cells (VSMC) (Block et al., 1991), and for interleukins in human mesangial cells (Roth et al., 1992). Two Ca(2+)-channel blockers, Manidipine (Roth et al., 1992) and Verapamil (Walz et al., 1990) have been shown to induce the expression of the gene coding for interleukin-6 (IL-6). Here we demonstrate that the four Ca(2+)-channel blockers, Amlodipine, Felodipine, Isradipine and Manidipine, at nanomolar concentrations, activate the transcription of the genes encoding IL-6 and IL-8 in primary human VSMC and fibroblasts. Ca(2+)-channel blocker-induced transcription is subsequently followed by secretion of the two ILs into the growth medium of the cells. In addition, we compared the action of the Ca(2+)-channel blockers with that of propranolol, a beta-adrenoceptor antagonist, or with furosemide, a diuretic, all of which are known to lower blood pressure. However, in contrast to the dihydropyridines, the two latter drugs failed to affect the expression of the two IL genes.

Adrenergic beta-Antagonists↗
PubMed1995

Quantitative determination of high-, low-, and very-low-density lipoproteins and lipoprotein(a) by agarose gel electrophoresis and enzymatic cholesterol staining.

Quantification of lipoprotein cholesterol was performed by enzymatic staining of cholesterol in a new agarose gel electrophoresis method that allows the separation of LDL, VLDL, HDL, and lipoprotein(a) [Lp(a)]. Lp(a) shows an electrophoretic mobility clearly distinct from VLDL and HDL. The total CVs of lipoprotein cholesterol varied between 2.7% and 3.9% for LDL, 7.8% and 23.2% for VLDL, 5.2% and 9.5% for HDL, and 6.8% and 16.4% for Lp(a). Comparison of LDL-, VLDL-, and HDL-cholesterol concentrations with the results of a combined ultracentrifugation and precipitation technique gave correlation coefficients of 0.961, 0.947, and 0.918, respectively; comparison of Lp(a)-cholesterol values with those of a nephelometric Lp(a) assay gave r = 0.906. The new electrophoretic assay has several advantages: It allows the quantification of Lp(a)-cholesterol; VLDL-cholesterol is not affected by Lp(a)-cholesterol; and the LDL-cholesterol fraction does not contain Lp(a)-cholesterol, as happens with LDL-cholesterol determined by ultracentrifugation and precipitation.

Adult↗
PubMed1995

Direct determination of lipoprotein(a) cholesterol by ultracentrifugation and agarose gel electrophoresis with enzymatic staining for cholesterol.

Lipoprotein(a) [(Lp(a)], a low-density lipoprotein (LDL)-like particle, contains in addition to LDL a specific protein component, apolipoprotein(a) [apo(a)]. Conventionally, Lp(a) has been measured by immunological methods that distinguish between Lp(a) and LDL by dealing with apo(a) as an antigen. We describe a new method to determine Lp(a) on the basis of its cholesterol content. Very-low-density lipoproteins were removed from serum by preparative ultracentrifugation at a density of 1.006 kg/L. The infranate was subjected to agarose gel electrophoresis to separate Lp(a) and LDL. Lp(a) cholesterol was then determined by direct enzymatic staining for cholesterol. On electrophoresis of the > 1.006 kg/L (bottom) fraction, Lp(a) migrates to the pre-beta position, regardless of the genetic apo(a) isoform. The interassay CVs of Lp(a) cholesterol determinations ranged from 6.9% to 11.5%, and the results correlated well with the Lp(a) concentrations measured by immunonephelometry (r = 0.937). There was an inverse relation between the molecular mass of the genetically determined apo(a) isoforms and Lp(a) cholesterol concentrations. Patients with angiographically proven coronary artery disease (CAD) had significantly more Lp(a) cholesterol than healthy controls did. The ratio of Lp(a) cholesterol to immunologically determined Lp(a) tended to be lower in CAD patients, suggesting that Lp(a) particles contained less cholesterol than apo(a). In addition, the new method allows determination of LDL cholesterol without contamination by Lp(a).

Adult↗
PubMed1995

Determination of triglycerides in lipoproteins separated by agarose gel electrophoresis.

We developed a simple method for the quantitation of triglycerides in electrophoretically separated lipoproteins by specific enzymatic staining. After electrophoresis, glycerol is liberated from triglycerides by the action of cholesterol esterase. Glycerol is oxidized by a sequence of enzymatic reactions. Due to the presence of triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase in the reaction mixture, two moles of the precipitating dye formazane are generated per mole glycerol. The relative amounts of alpha, pre-beta, and beta lipoproteins are determined by densitometric scanning at 570 nm. Absolute triglyceride concentrations of the respective lipoprotein fractions are calculated from total triglycerides. When tested with purified very low density lipoproteins, the electrophoresis assay was linear between 0.08 and 6.5 g/l pre-beta lipoprotein triglycerides. The intra-assay and inter-assay coefficients of variation were between 5.2% and 9.8%, and between 3.2% and 12.9%, respectively. Comparison of the electrophoresis method with a combined ultracentrifugation/precipitation method in 172 sera resulted in the following correlation coefficients: alpha lipoprotein versus high density lipoprotein triglycerides, r = 0.847; pre-beta lipoprotein versus very low density lipoprotein triglycerides, r = 0.989; beta lipoprotein versus low density lipoprotein triglycerides, r = 0.815. This method is easy to perform, and is a precise and accurate technique for the determination of lipoprotein triglycerides. It is the first reliable method that allows the direct quantification of LDL triglycerides without ultracentrifugation.

Analysis of Variance↗
PubMed1995

Pseudo-pseudohypertriglyceridemia: a case of increased free glycerol without evidence for glycerol kinase deficiency.

High concentrations of glycerol in plasma may result in overestimation of triglycerides in chemical and enzymatic assays. Known causes of increased glycerol concentrations in blood include glycerol-contaminated blood-collector tubes and pseudohypertriglyceridemia, a condition caused by genetic defects in the gene for glycerol kinase. We report a patient with sudden hearing loss who presented with an increased blood glycerol concentration after undergoing an oral glycerol test.

Adult↗